Compositions and methods for drug sensitization of parasites

ABSTRACT

Compositions and methods for inhibiting and/or sensitizing or re-sensitizing a parasite to an antiparasitic drug are provided. The compositions can comprise a an arylphenoxypropionate derivative, an aryloxyphenoxyacetate derivative, an aryloxyphenylacetate derivative, one or more substituted quinols, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, or a combination thereof in an amount and formulation sufficient to sensitize the parasite to the drug, treating infection of a patient by a parasite with a drug, or to prevent symptomatic infection of a patient by a parasite with a drug.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase of International Application No.PCT/US2016/048890 filed Aug. 26, 2016 which claims priority to U.S.Provisional Patent Application Ser. No. 62/210,224, filed Aug. 26, 2015,all of which are hereby incorporated by reference in their entirety.

TECHNICAL FIELD

The present disclosure relates to compositions for parasite inhibitionand/or sensitization or re-sensitization of a parasite to another drugor combination of drugs. In particular, it relates to compositionsincluding one or more arylphenoxypropionate derivatives, such as, butnot limited to, quizalofop, fenoxaprop, proquizalofop, and haloxyfop,one or more aryloxyphenoxyacetate derivatives, one or morearyloxyphenylacetate derivatives, and one or more substituted quinols,and combinations thereof. The present disclosure also relates to methodsof parasite inhibition and/or sensitizing or re-sensitizing a parasiteto another drug or combination of drugs by applying morearylphenoxypropionate derivatives to the parasite.

BACKGROUND

Parasitic infection is treated, or prevented, by the administration of adrug or drugs, such as xenobiotic chemotherapeutic drugs, to asusceptible or infected host organism. Effective treatment of parasiticinfection by drug administration is frequently impaired, however, due toresistance of the parasite to the drug. Such resistance can be“inherent” to the parasite in the sense that the susceptibility of theparasite to the drug has not increased due to widespread use of thedrug. Commonly, however, drug resistance of infectious parasites isobserved due to evolved resistance associated with widespread treatmentwith the drug and associated selection pressure for resistantphenotypes. Currently, many infectious parasites are completely orhighly resistant to available drugs and drug combinations, and parasitesstill susceptible to available drugs require treatment with greaterdoses than previously required, such that complete or effectivelycomplete resistance is foreseeable.

For example, chloroquine resistance in certain species ofmalaria-causing Plasmodium parasites is so widespread that alternativeor combination anti-malarial therapies are now required, and manyparasitic species, including malaria-causing Plasmodium species, are nowmulti-drug resistant. As a further example, the incidence of parasiteresistance to avermectins, a widely used class of nematicides,acaridices and insecticides in veterinary and human medicine and plantprotection, is increasing.

Resistance of infectious parasites to anti-parasitic drugs can beavoided or lessened by rendering the parasites more sensitive to one ormore drugs. The calcium channel blocker Verapramil, for example, hasbeen evaluated for its effect on sensitization of parasites toxenobiotics. However, safe, economical, and effective methods forsensitizing parasites in such a manner are lacking.

SUMMARY

Compositions and methods for inhibiting and/or sensitizing orre-sensitizing a parasite to an antiparasitic drug are provided. Thecompositions can comprise a an arylphenoxypropionate derivative, anaryloxyphenoxyacetate derivative, an aryloxyphenylacetate derivative,one or more substituted quinols, or a pharmaceutically acceptable salt,hydrate, or prodrug thereof, or a combination thereof in an amount andformulation sufficient to sensitize the parasite to the drug, treatinginfection of a patient by a parasite with a drug, or to preventsymptomatic infection of a patient by a parasite with a drug.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete understanding of the present embodiments and advantagesthereof may be acquired by referring to the following description takenin conjunction with the accompanying drawings, which depict embodimentsof the present disclosure, and in which like numbers refer to similarcomponents, and in which:

FIG. 1 is a graph of oocyst numbers vs. days post infection in mice withCryptosporodosis treated with a control or test compounds;

FIG. 2 is a graph of fecal volume vs. days post infection in calves withCryptosporodosis treated with a control or test compound;

FIG. 3 is a graph of urine volume vs. days post infection in calves withCryptosporodosis treated with a control or test compound;

FIG. 4 is a graph of overall clinical evaluation vs. days post infectionin calves with Cryptosporodosis treated with a control or test compound;

FIG. 5 is a graph of fecal consistency vs. days post infection in calveswith Cryptosporodosis treated with a control or test compound;

FIG. 6 is a graph of percent weight change over a trial period in calveswith Cryptosporodosis treated with a control or test compound; and

FIG. 7 is a graph of lesion scores for duodenal lesions in broilerchicks with coccidiosis that were untreated or treated with a control ortest compound.

DETAILED DESCRIPTION

The present disclosure relates to compositions and methods forinhibition and/or drug-sensitization of a parasite. These compositionsand methods are described in further detail below.

Unless otherwise indicated by the specific context of thisspecification, a parasite can include any type of parasite, or any partthereof. Furthermore, it can include a parasite in a host organism, oroutside a host organism, such as in the environment occupied by anorganism susceptible to infection by the parasite. The organism or hostorganism can be any animal. By way of example, and not limitation, theorganism or host organism can be a mammal, such as a human, a pet mammalsuch as a dog or cat, an agricultural mammal, such as a horse, cow, pig,sheep, or goat, or a zoo mammal.

Although many embodiments herein are described with reference to asingle parasite, the present disclosure is not so limited. The presentdisclosure encompasses, for example, infections of a single host animalwith a plurality of parasites of the same species and with a pluralityof parasites of different species, concurrently or otherwise. Theseembodiments and others will be readily apparent to one of ordinary skillin the art in view of the present disclosure.

Drug-sensitization, unless otherwise indicated by the specific contextof this specification, can include increased sensitivity to a drug,decreased resistance to a drug, or potentiation of a drug's activity orefficacy. Any effect can be measured using any methods accepted in theart. In certain embodiments, drug-sensitization can be determined by anincreased ability of the drug to inhibit a parasite. Parasiticinhibition can include killing the parasite, rendering the parasite moresusceptible to the immune system of a host organism, arresting theparasite in a phase of its life cycle that is relatively benign withrespect to the host organism, reducing the rate of propagation of theparasite in the host organism, or otherwise negatively affecting aparasite. An increased ability of the drug to inhibit a parasite can bedemonstrated by, for example, an ability to inhibit the cell with areduced amount of drug or in a shorter period of time than in theabsence of drug-sensitization. In the case of drug-resistant parasites,which include parasites with inherent or acquired resistance,drug-sensitization can result in a renewed, restored, restored or newlyacquired ability of the drug to inhibit a parasite or type of parasite.

Administration to a parasite, unless otherwise indicated by the specificcontext of this specification, can include administration directly to aparasite or indirect administration to a parasite, such as by direct orindirect administration to a host organism infected by the parasite orby prophylactic administration to an organism susceptible to infectionby the parasite, or such as by administration to the environment of theparasite, such as by administration to an environment of the parasite.By way of example and not limitation, administration to a parasite caninclude, in addition to directly contacting the parasite with thecomposition administered, oral, enteral, and parenteral administrationto an infected or susceptible host, as well as administration of thecompound to a body of or source of water, for example, in which theparasite resides or will reside, as well as administration of thecompound to a substrate or fomite upon which the parasite resides orwill reside, or upon which another host or susceptible host organismresides or will reside, such as, for example, a mosquito netting, aportion of a plant such as a leaf, or a consumer product that can comeinto close contact with the skin of a human or animal, such as abedsheet, a protective athletic garment, or a harness. By way of furtherexample, the compositions of the present disclosure can be administeredto a susceptible animal or infected host in the form of aerosolizedparticles, e.g., by way of aerosolizer, nebulizer or other like device,or transdermally, or transbucally, or sublingually, or by subcutaneousadministration, or any other method of drug delivery, and anycombination thereof.

Compositions

The present disclosure includes parasite drug-sensitizationcompositions, including one or more arylphenoxypropionate derivatives,one or more aryloxyphenoxyacetate derivatives, one or morearyloxyphenylacetate derivatives, one or more substituted quinols, orpharmaceutically acceptable salts, hydrates, or prodrugs thereof, orcombinations thereof.

In certain embodiments, the present disclosure providesarylphenoxypropionate derivatives according to one of the followingstructures:

and enantiomers of the general structures.

In certain embodiments, the present disclosure providesaryloxyphenoxyacetate derivatives according to the following structure:

wherein R₁ is selected from —OR₅, —NR₆R₇ and —NH—SO₂—R₈ groups, R₂ andR₃ are independently selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, and heteroaryl groups; or R₂ and R₃ together are acycloalkyl group; R₄ is selected from the group consisting of aryl,heteroaryl, bicycloaryl, and bicycloheteroaryl groups optionallyadditionally substituted with from zero to four substitutions selectedindependently from halogen, hydroxyl, alkyl, alkoxy, nitril, nitro,amino, alkylamino, dialkylamino, dialkylaminoalkyl, carboxy, acyl,carboxamido, alkylsulfoxide, acylamino, phenyl, benzyl, phenoxy, andbenzyloxy groups; R₅ is selected from hydrogen or an alkyl, aryl, orbenzyl group that is optionally additionally substituted with analkyloxy, alkylamino, dialkylamino, or acylamino group; R₆ and R₇ areindependently selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy groups; or R₆and R₇ together are a cycloalkyl or heterocycloalkyl group; and R₈ is analkyl or aryl group optionally substituted with halogen.

In certain embodiments, the present disclosure providesaryloxyphenylacetate derivatives according to the following structure:

wherein R₁ is selected from —OR₅, —NR₆R₇ and —NH—SO₂—R₈ groups, R₂ andR₃ are independently selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, and heteroaryl groups; or R₂ and R₃ together are acycloalkyl group; R₄ is selected from the group consisting of aryl,heteroaryl, bicycloaryl, and bicycloheteroaryl groups optionallyadditionally substituted with from zero to four substitutions selectedindependently from halogen, hydroxyl, alkyl, alkoxy, nitril, nitro,amino, alkylamino, dialkylamino, dialkylaminoalkyl, carboxy, acyl,carboxamido, alkylsulfoxide, acylamino, phenyl, benzyl, phenoxy, andbenzyloxy groups; R₅ is selected from hydrogen or an alkyl, aryl, orbenzyl group that is optionally additionally substituted with analkyloxy, alkylamino, dialkylamino, or acylamino group; R₆ and R₇ areindependently selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkoxy groups; or R₆and R₇ together are a cycloalkyl or heterocycloalkyl group; and R₈ is analkyl or aryl group optionally substituted with halogen.

In certain embodiments, the present disclosure provides substitutedquinols according to the following structure:

wherein R₉ is selected from nitril, hydroxyl, heterocycloaryl andalkyloxy groups; and R₄ is selected from the group consisting of aryl,heteroaryl, bicycloaryl, and bicycloheteroaryl groups optionallyadditionally substituted with from zero to four substitutions chosenindependently from the group consisting of halogen, hydroxyl, alkyl,alkyloxy, nitril, nitro, amino, alkylamino, dialkylamino,dialkylaminoalkyl, carboxy, acyl, carboxamido, alkylsulfoxide,acylamino, phenyl, benzyl, phenoxy, and benzyloxy groups.

Specific compounds of the invention include those named in Table 1 andcharacterized in the examples herein.

TABLE 1 Arylphenoxypropionate Derivatives WuXi-N8

1-{5-[(6-chloro-1,3-benzothiazol-2-yl)oxy]pyridin-2-yl}-3-(propan-2-yl)urea WuXi-N7

1-{6-[(6-chloro-1,3-benzothiazol-2-yl)oxy]pyridazin-3-yl}-3-(propan-2-yl)urea WuXi-N6

1-{6-[(6-chloro-1,3-benzothiazol-2-yl)oxy]pyridin-3-yl}-3-(propan-2-yl)urea WUXI-N5

3-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]piperidin-1-yl}-N-methoxypropanamide WUXI-N4

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]piperidin-1-yl}-N-methoxyacetamide quizalofop-p- ethyl

ethyl (2R)-2-{4-[(6-chloroquinoxalin-2- yl)oxy]phenoxy}propanoatequizalofop-p

(2R)-2-{4-[(6-chloroquinoxalin-2- yl)oxy]phenoxy}propanoic acidpropaquizafop

2-{[(propan-2-ylidene)amino]oxy}ethyl 2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}propanoate NZ-578

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-(2-methanesulfonylethyl)propanamide NZ-577

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-(oxetan-3-yl)acetamide NZ-576

4-(2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}acetyl)-1λ⁶,4-thiomorpholine-1,1- dione NZ-575

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(morpholin-4-yl)ethan-1-one NZ-574

1-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-3-(oxetan-3-yl)ureaNZ-573

N-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-1,1-dioxo-1λ⁶,4-thiomorpholine- 4-carboxamide NZ-572

N-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}morpholine-4-carboxamide NZ-564

1-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-(oxetan-3-yl)cyclopropane-1- carboxamide NZ-563

4-(1-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}cyclopropanecarbonyl)-1λ⁶,4- thiomorpholine-1,1-dioneNZ-562

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-(5-oxopyrrolidin-3-yl)propanamide NZ-561

6-chloro-2-{4-[1-(morpholine-4- carbonyl)cyclopropyl]phenoxy}-1,3-benzothiazole NZ-560

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-(3-hydroxycyclobutyl)propanamide NZ-559

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-N,N-bis(2-hydroxyethyl)propanamide NZ-558

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-[2-(hydroxymethyl)morpholin- 4-yl]propan-1-one NZ-557

N-{2-[bis(2-hydroxyethyl)amino]ethyl}-2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}propanamide NZ-556

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-{2-[(2-hydroxyethyl)(methyl)amino]ethyl}propanamide NZ-555

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-[3-(hydroxymethyl)morpholin- 4-yl]propan-1-one NZ-554

4-(2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}propanoyl)morpholine-2- carboxamide NZ-553

4-(2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}propanoyl)-1λ⁶,4-thiomorpholine- 1,1-dione NZ-550

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-N-[2-(methylamino)ethyl]propanamide NZ-548

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-[2-(methylamino)ethyl]propanamide NZ-547

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-[2-(dimethylamino)ethyl]-N- methylpropanamide NZ-546

N-[2-(dimethylamino)ethyl]-2,2-difluoro-2-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}acetamide NZ-545

2,2-difluoro-2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(4-methylpiperazin-1-yl)ethan- 1-one NZ-544

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-(oxolan-3-yl)propanamide NZ-543

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-(oxetan-3-yl)propanamide NZ-542

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-(1,3-dimethoxypropan-2- yl)propanamide NZ-541

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-(2-methoxyethyl)propanamide NZ-539

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-cyclobutylpropanamide NZ-538

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-cyclopropylpropanamide NZ-537

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-1-(piperazin-1-yl)propan-1-one NZ-536

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-N-(1,3-dihydroxypropan-2-yl)propanamide NZ-535

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-N-[2-(dimethylamino)ethyl]propanamide NZ-534

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-N-(2,3-dihydroxypropyl)propanamide NZ-533

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-N-(2-hydroxyethyl)propanamide NZ-532

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-N- (propan-2-yl)propanamideNZ-531

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-N- methylpropanamide NZ-530

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-N,N- dimethylpropanamideNZ-529

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-1-(morpholin-4-yl)propan-1-one NZ-522

6-chloro-2-{4-[1-(4-methylpiperazine-1-carbonyl)cyclopropyl]phenoxy}-1,3- benzothiazole NZ-521

1-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-methylcyclopropane-1- carboxamide NZ-518

N-(2-aminoethyl)-2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}propanamide NZ-516

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-[2-(dimethylamino)ethyl]propanamide NZ-513

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-[4-(oxetan-3-yl)piperazin-1- yl]propan-1-one NZ-512

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-1-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]propan-1-one NZ-511

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(4-cyclopropylpiperazin-1- yl)propan-1-one NZ-510

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-[4-(propan-2-yl)piperazin-1- yl]propan-1-one NZ-509

N-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}piperazine-1-carboxamide NZ-506

4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl4-methylpiperazine-1-carboxylate NZ-505

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}acetamide NZ-500

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]-2- fluorophenyl}acetamideNZ-496

2-{4-[(5,6-difluoro-1,3-benzothiazol-2-yl)oxy]-2- fluorophenyl}acetamideNZ-490

2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(pyrrolidin-1-yl)ethan-1-one NZ-489

2-{4-[(5,6-difluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(piperazin-1-yl)propan-1-one NZ-485

2-{4-[(5,6-difluoro-1,3-benzothiazol-2- yl)oxy]phenyl}acetamide NZ-484

2-{2-fluoro-4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}acetamideNZ-481

2-{4-[(5,6-difluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(piperidin-1-yl)ethan-1-one NZ-479

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(piperazin-1-yl)ethan-1-one NZ-477

2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(piperazin-1-yl)propan-1-one NZ-476

2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(4-methylpiperazin-1-yl)ethan- 1-one NZ-475

N-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-4-methylpiperazine-1-carboxamide NZ-472

2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(piperazin-1-yl)ethan-1-one NZ-471

2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(piperidin-1-yl)ethan-1-one NZ-469

tert-butyl 4-(2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}acetyl)piperazine-1-carboxylate NZ-467

2-{2-fluoro-4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(4-methylpiperazin-1-yl)ethan- 1-one NZ-466

2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(4-methylpiperazin-1- yl)propan-1-one NZ-465

2-{4-[(5,6-difluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(4-methylpiperazin-1- yl)propan-1-one NZ-464

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(4-methylpiperazin-1-yl)ethan- 1-one NZ-460

2-{4-[(6-chloroquinoxalin-2-yl)oxy]-2,6-difluorophenyl}-N-methylacetamide NZ-459

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]-2,6-difluorophenyl}-N-methylacetamide NZ-458

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]-2,6- difluorophenyl}aceticacid NZ-450

2-{4-[(5,6-difluoro-1,3-benzothiazol-2-yl)oxy]-2,6-difluorophenyl}-N-methylacetamide NZ-446

N-cyclopropyl-2-{2-fluoro-4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}acetamide NZ-440

2-{4-[(5,6-difluoro-1,3-benzothiazol-2-yl)oxy]-2- fluorophenyl}aceticacid NZ-438

N-(carbamoylmethyl)-2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}acetamide NZ-433

2-{2,6-difluoro-4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-methylacetamide NZ-427

N-(2-aminoethyl)-2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}acetamide NZ-426

2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-(2-hydroxyethyl)acetamide NZ-425

N-[2-(dimethylamino)ethyl]-2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}acetamide NZ-420

N-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}acetamide NZ-419

2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]-2-oxo-1,2-dihydropyridin-1-yl}-N- methylacetamide NZ-418

2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]-2-oxo-1,2-dihydropyridin-1-yl}acetic acid NZ-417

2-amino-N-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}acetamideNZ-416

3-amino-N-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}propanamideNZ-415

tert-butyl N-[({4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}carbamoyl)methyl]carbamate NZ-414

tert-butyl N-[2-({4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}carbamoyl)ethyl]carbamate NZ-413

4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]aniline NZ-412

tert-butyl N-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}carbamateNZ-411

2-{4-[(5,6-difluoro-1,3-benzothiazol-2-yl)oxy]-2-fluorophenyl}-N-methylacetamide NZ-410

2-{2-fluoro-4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-methylacetamide NZ-409

2-{4-[(5,6-difluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(4-methylpiperazin-1-yl)ethan- 1-one NZ-408

2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]-2-hydroxyphenyl}-N-methylpropanamide NZ-407

2-{4-[(5,6-difluoro-1,3-benzothiazol-2-yl)oxy]-2-hydroxyphenyl}-N-(propan-2-yl)acetamide NZ-406

2-{2-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]-4-hydroxyphenyl}-N-(propan-2-yl)acetamide NZ-405

2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]-2-hydroxyphenyl}-N-(propan-2-yl)acetamide NZ-404

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]-2-oxo-1,2-dihydropyridin-1-yl}-N-(propan-2- yl)acetamide NZ-403

2-{4-[(5,6-difluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-(propan-2-yl)acetamide NZ-402

2-{4-[(6-chloroquinoxalin-2-yl)oxy]-2- hydroxyphenyl}-N-methylacetamideNZ-401

2-{4-[(5,6-difluoro-1,3-benzothiazol-2-yl)oxy]-2-hydroxyphenyl}-N-methylacetamide NZ-400

2-{4-[(5,6-difluoro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-methylacetamideNZ-399

2-{4-[(5,6-difluoro-1,3-benzothiazol-2- yl)oxy]phenyl}acetic acid NZ-398

methyl 2-{4-[(5,6-difluoro-1,3-benzothiazol-2- yl)oxy]phenyl}acetateNZ-397

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]-2-oxo-1,2-dihydropyridin-1-yl}acetic acid NZ-396

methyl 2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]-2-oxo-1,2-dihydropyridin-1-yl}acelate NZ-395

2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]-2-hydroxyphenyl}-N-methylacetamide NZ-394

2-{4-[(5,6-dichloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-methylpropanamide NZ-393

1-{4-[(5,6-dichloro-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(propan-2-yl)urea NZ-392

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]-2-methoxyphenyl}-N-methylacetamide NZ-391

1-{5-[(6-chloro-1,3-benzothiazol-2-yl)oxy]-1-oxo-1λ⁵-pyridin-2-yl}-3-(propan-2-yl)urea NZ-390

2-{2-[(6-chloro-1,3-benzothiazol-2-yl)oxy]-4-hydroxyphenyl}-N-methylacetamide NZ-389

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]-2-hydroxyphenyl}-N-methylacetamide NZ-388

1-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-methyl-3-(propan-2-yl)urea NZ-387

2-{4-[(5,6-difluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-methylpropanamide NZ-386

2-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-methylpropanamideNZ-385

2-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-methylacetamideNZ-383

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-methylacetamideNZ-382

1-{4-[(5,6-difluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(propan-2-yl)urea NZ-381

1-(4-{[6-(hydroxymethyl)-1,3-benzothiazol-2-yl]oxy}phenyl)-3-(propan-2-yl)urea NZ-380

1-{4-[(6-methanesulfonyl-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(propan-2-yl)urea NZ-379

3-(propan-2-yl)-1-(4-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]oxy}phenyl)urea NZ-378

ethyl 2-(4-{[(propan-2- yl)carbamoyl]amino}phenoxy)-1,3-benzothiazole-6-carboxylate NZ-377

1-{4-[(6-cyano-1,3-benzothiazol-2- yl)oxy]phenyl}-3-(propan-2-yl)ureaNZ-376

1-{4-[(5-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-3-(propan-2-yl)ureaNZ-374

1-{4-[(4-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}-3-(propan-2-yl)ureaNZ-373

1-{4-[(5-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}-3-(propan-2-yl)ureaNZ-372

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-(2,3-dihydroxypropyl)propanamide NZ-371

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-(1,3-dihydroxypropan-2- yl)propanamide NZ-370

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-(2-hydroxyethyl)propanamide NZ-369

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-methylpropanamideNZ-368

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N,N-dimethylpropanamide NZ-366

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(4-methylpiperazin-1- yl)propan-1-one NZ-365

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(morpholin-4-yl)propan-1-one NZ-364

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-1-(piperazin-1-yl)propan-1-one NZ-363

1-{4-[(6-nitro-1,3-benzothiazol-2- yl)oxy]phenyl}-3-(propan-2-yl)ureaNZ-362

1-{4-[(6-hydroxy-1,3-benzothiazol-2- yl)oxy]phenyl}-3-(propan-2-yl)ureaNZ-361

1-{4-[(6-methoxy-1,3-benzothiazol-2- yl)oxy]phenyl}-3-(propan-2-yl)ureaNZ-360

1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-3- (propan-2-yl)urea NZ-359

1-{4-[(6-bromo-1,3-benzothiazol-2- yl)oxy]phenyl}-3-(propan-2-yl)ureaNZ-358

1-{4-[(6-methyl-1,3-benzothiazol-2- yl)oxy]phenyl}-3-(propan-2-yl)ureaNZ-357

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N,2-dimethoxyacelamide NZ-356

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-2-methoxyacetic acidNZ-355

methyl 2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-2-methoxyacetate NZ-354

1-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-3,3-dimethylureaNZ-353

1-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-3-methylurea NZ-352

4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]aniline NZ-351

tert-butyl N-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}carbamateNZ-350

1-({4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}methyl)-3-methylureaNZ-349

1-({4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}methyl)-3,3-dimethylurea NZ-348

{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}methanamine NZ-347

tert-butyl N-({4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}methyl)carbamate NZ-346

1-{4-[(6-chloroquinolin-2-yl)oxy]phenyl}-3- (propan-2-yl)urea NZ-345

1-{4-[(6-fluoroquinoxalin-2-yl)oxy]phenyl}-3- (propan-2-yl)urea NZ-344

1-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-3- methoxyurea NZ-343

1-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-3,3- dimethylurea NZ-342

1-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-3- methylurea NZ-341

1-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}imidazolidin-2-oneNZ-338

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-2-hydroxy-N-methoxyacetamide NZ-337

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-2-hydroxyacetic acidNZ-336

methyl 2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-2-hydroxyacetate NZ-335

N-methoxy-2-{4-[(6-methoxy-1,3-benzothiazol- 2-yl)oxy]phenyl}propanamideNZ-334

2-{4-[(6-methoxy-1,3-benzothiazol-2- yl)oxy]phenyl}propanoic acid NZ-333

methyl 2-{4-[(6-methoxy-1,3-benzothiazol-2- yl)oxy]phenyl}propanoateNZ-332

1-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}-3-(propan-2-yl)ureaNZ-331

1-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-3-(propan-2-yl)ureaNZ-330

2-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-methoxypropanamideNZ-329

2-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}propanoic acid NZ-328

methyl 2-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}propanoateNZ-327

2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-(propan-2-yl)propanamide NZ-326

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-N- (propan-2-yloxy)acetamideNZ-325

(Z)-2-{4-[(6-chloroquinoxalin-2- yl)oxy]phenoxy}-N-methoxyethenecarbonimidoyl chloride NZ-323

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-N-(cyclopropylmethoxy)acetamide NZ-322

1-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-3- (propan-2-yl)urea NZ-321

tert-butyl N-{4-[(6-chloroquinoxalin-2- yl)oxy]phenyl}carbamate NZ-320

N-methoxy-2-oxo-7-phenoxy-2H-chromene-3- carboxamide NZ-319

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenoxy}-N-methoxy-2-methylpropanamide NZ-318

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenoxy}-2-methylpropanoicacid NZ-317

methyl 2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenoxy}-2-methylpropanoate NZ-316

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-N-methoxy-2-methylpropanamide NZ-315

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-2- methylpropanoic acidNZ-314

methyl 2-{4-[(6-chloroquinoxalin-2- yl)oxy]phenoxy}-2-methylpropanoateNZ-313

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-methoxypropanamideNZ-312

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}propanoic acid NZ-311

methyl 2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}propanoateNZ-310

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-N- methoxypropanamide NZ-309

2-{4-[(6-chloroquinoxalin-2- yl)oxy]phenyl}propanoic acid NZ-308

methyl 2-{4-[(6-chloroquinoxalin-2- yl)oxy]phenyl}propanoate NZ-307

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-N- (propan-2-yl)acetamideNZ-306

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-N- ethylacetamide NZ-305

2-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenoxy}-N-methoxyacetamideNZ-304

2-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenoxy}acetic acid NZ-303

methyl 2-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenoxy}acetate NZ-302

methyl 2-{4-[(6-chloro-1,3-benzoxazol-2- yl)oxy]phenyl}acetate NZ-301

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}-N- methoxyacetamide NZ-300

2-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-methoxyacetamideNZ-299

2-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}acetic acid NZ-298

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenyl}acetic acid NZ-297

methyl 2-{4-[(6-chloroquinoxalin-2- yl)oxy]phenyl}acetate NZ-296

(2R)-2-{4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenoxy}-N-methoxypropanamide NZ-295

(2R)-2-{4-[(6-chloroquinoxalin-2- yl)oxy]phenoxy}-N-methoxypropanamideNZ-294

methyl 2-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenyl}acetate NZ-293

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}-N-methoxyacetamideNZ-292

6-chloro-2-phenoxy-1,3-benzothiazole NZ-291

6-chloro-2-(3-methylphenoxy)-1,3- benzothiazole NZ-290

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-N- methoxy-N-methylacetamideNZ-289

(2R)-2-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenoxy}-N-methoxypropanamide NZ-288

4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]benzoic acid NZ-287

2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}acetic acid NZ-286

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-N- hydroxyacetamide NZ-285

methyl 4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]benzoate NZ-284

methyl 2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}acetate NZ-283

(2E)-3-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}prop-2-enoic acidNZ-282

3-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}propanoic acid NZ-281

methyl (2E)-3-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}prop-2-enoate NZ-280

methyl 3-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenyl}propanoateNZ-279

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-N- hydroxy-N-methylacetamideNZ-278

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-1-(4-methylpiperazin-1-yl)ethan-1-one NZ-277

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-1-(piperazin-1-yl)ethan-1-one NZ-276

N-(benzenesulfonyl)-2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}acetamide NZ-275

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-N-trifluoromethanesulfonylacetamide NZ-274

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-N- methoxyacetamide NZ-273

6-chloro-2-[4-(1H-imidazol-2- ylmethoxy)phenoxy]quinoxaline NZ-272

6-chloro-2-[4-(2,2- diethoxyethoxy)phenoxy]quinoxaline NZ-271

6-chloro-2-[4-(1,3-oxazol-2- ylmethoxy)phenoxy]quinoxaline NZ-270

6-chloro-2-{4-[(1-methyl-1H-1,2,3,4-tetrazol-5-yl)methoxy]phenoxy}quinoxaline NZ-269

6-chloro-2-{4-[(2-methyl-2H-1,2,3,4-tetrazol-5-yl)methoxy]phenoxy}quinoxaline NZ-268

6-chloro-2-[4-(1H-1,2,3,4-tetrazol-5- ylmethoxy)phenoxy]quinoxalineNZ-267

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-N- methylacetamide NZ-266

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-1-(morpholin-4-yl)ethan-1-one NZ-265

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-1-(piperidin-1-yl)ethan-1-one NZ-264

1-{4-[(6-chloroquinoxalin-2- yl)oxy]phenoxy}propan-2-ol NZ-263

2-{4-[(6-chloroquinoxalin-2- yl)oxy]phenoxy}acetonitrile NZ-262

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}- N,N-dimethylacetamideNZ-261

(2R)-2-{4-[(6-nitro-1,3-benzothiazol-2- yl)oxy]phenoxy}propanoic acidNZ-260

ethyl (2R)-2-{4-[(6-nitro-1,3-benzothiazol-2- yl)oxy]phenoxy}propanoateNZ-259

2-{4-[(6-chloroquinoxalin-2-yl)oxy]phenoxy}-N- methanesulfonylacetamideNZ-258

2-{4-[(6-chloroquinoxalin-2- yl)oxy]phenoxy}acetamide NZ-257

2-{4-[(6-chloroquinoxalin-2- yl)oxy]phenoxy}acetic acid NZ-256

methyl 2-{4-[(6-chloroquinoxalin-2- yl)oxy]phenoxy}acetate NZ-255

(2R)-2-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenoxy}propanoic acidNZ-254

(2R)-2-[4-(1,3-benzothiazol-2- yloxy)phenoxy]propanoic acid NZ-253

(2R)-2-{4-[(6-bromo-1,3-benzothiazol-2- yl)oxy]phenoxy}propanoic acidNZ-252

ethyl (2R)-2-[4-(1,3-benzothiazol-2- yloxy)phenoxy]propanoate NZ-251

ethyl (2R)-2-{4-[(6-fluoro-1,3-benzothiazol-2- yl)oxy]phenoxy}propanoateNZ-250

ethyl (2R)-2-{4-[(6-bromo-1,3-benzothiazol-2- yl)oxy]phenoxy}propanoateNZ-247

(2R)-2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenoxy}propanoic acidNZ-246

ethyl (2R)-2-{4-[(6-chloro-1,3-benzothiazol-2- yl)oxy]phenoxy}propanoatefenoxaprop-p- ethyl

ethyl (2R)-2-{4-[(6-chloro-1,3-benzoxazol-2- yl)oxy]phenoxy}propanoatefenoxaprop-p

2-{4-[(6-chloro-1,3-benzoxazol-2- yl)oxy]phenoxy}propanoic acid

The present disclosure also includes pharmaceutically acceptable salts,hydrates, prodrugs, and mixtures of any of the above compositions. Theterm “pharmaceutically acceptable salt” refers to salts whose counterion derives from pharmaceutically acceptable non-toxic acids and bases.

The arylphenoxypropionate derivatives, aryloxyphenoxyacetatederivatives, aryloxyphenylacetate derivatives, and substituted quinolswhich contain a basic moiety, such as, but not limited to an amine or apyridine or imidazole ring, may form salts with a variety of organic andinorganic acids. Suitable pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) base addition salts for the compounds of thepresent invention include inorganic acids and organic acids. Examplesinclude acetate, adipate, alginates, ascorbates, aspartates,benzenesulfonate (besylate), benzoate, bicarbonate, bisulfate, borates,butyrates, carbonate, camphorsulfonate, citrate, digluconates,dodecylsulfates, ethanesulfonate, fumarate, gluconate, glutamate,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrobromides,hydrochloride, hydroiodides, 2-hydroxyethanesulfonates, isethionate,lactate, maleate, malate, mandelate, methanesulfonate,2-naphthalenesulfonates, nicotinates, mucate, nitrate, oxalates,pectinates, persulfates, 3-phenylpropionates, picrates, pivalates,propionates, pamoate, pantothenate, phosphate, salicylates, succinate,sulfate, sulfonates, tartrate, p-toluenesulfonate, and the like.

The arylphenoxypropionate derivatives, aryloxyphenoxyacetatederivatives, aryloxyphenylacetate derivatives, and substituted quinolswhich contain an acidic moiety, such as, but not limited to a carboxylicacid, may form salts with variety of organic and inorganic bases.Suitable pharmaceutically acceptable base addition salts for thecompounds of the present invention include, but are not limited to,ammonium salts, metallic salts made from calcium, lithium, magnesium,potassium, sodium and zinc or organic salts made from lysine,N,N-dialkyl amino acid derivatives (e.g. N,N-dimethylglycine,piperidine-1-acetic acid and morpholine-4-acetic acid),N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), t-butylamine,dicyclohexylamine, hydrabamine, and procaine.

The arylphenoxypropionate derivatives, aryloxyphenoxyacetatederivatives, aryloxyphenylacetate derivatives, and substituted quinols,and salts thereof, may exist in their tautomeric form (for example, asan amide or imino ether). All such tautomeric forms are contemplatedherein as part of the present invention.

The compounds described herein may contain asymmetric centers and maythus give rise to enantiomers, diastereomers, and other stereoisomericforms. Each chiral center may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present invention is meant toinclude all such possible isomers, as well as, their racemic andoptically pure forms. Optically active (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques. When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers.

Compositions of the present disclosure may also include apharmaceutically acceptable carrier, in particular a carrier suitablefor the intended mode of administration, or salts, buffers, orpreservatives. Certain of the compounds disclosed herein are poorlysoluble in water. Accordingly, aqueous compositions of the presentdisclosure may include solubility enhancers. Compositions for oral usemay include components to enhance intestinal absorption. The overallformulation of the compositions may be based on the intended mode ofadministration. For instance, the composition may be formulated as apill or capsule for oral ingestion. In other examples, the compositionmay be encapsulated, such as in a liposome or nanoparticle.

Compositions of the present disclosure may contain a sufficient amountof one or more one or more arylphenoxypropionate derivatives, one ormore aryloxyphenoxyacetate derivatives, one or more aryloxyphenylacetatederivatives, one or more substituted quinols, or pharmaceuticallyacceptable salts, hydrates, or prodrugs thereof, or combinationsthereof, to cause inhibition of a mycobacterium to occur when thecomposition is administered to the mycobacterium. The amount can varydepending on other components of the composition and their effects ondrug availability in a patient, the amount of otherwise required toinhibit the mycobacterium, the intended mode of administration, theintended schedule for administration, any drug toxicity concerns,drug-drug interactions, such as interactions with other medications usedby the patient, or the individual response of a patient. Manycompositions may contain an amount well below levels at which toxicityto the patient becomes a concern.

The amount of arylphenoxypropionate derivative, aryloxyphenoxyacetatederivative, aryloxyphenylacetate derivative, substituted quinol, orpharmaceutically acceptable salt, hydrate, or prodrug thereof, orcombination thereof, present in a composition may be measured in any ofa number of ways. The amount may, for example, express concentration ortotal amount. Concentration may be for example, weight/weight,weight/volume, moles/weight, or moles/volume. Total amount may be totalweight, total volume, or total moles. Typically, the amount may beexpressed in a manner standard for the type of formulation or dosingregimen used.

Parasite Drug Sensitization and Inhibition Methods

The present disclosure also includes drug-sensitization and/orinhibition methods in which a composition comprising one or morearylphenoxypropionate derivatives, one or more aryloxyphenoxyacetatederivatives, one or more aryloxyphenylacetate derivatives, one or moresubstituted quinols, or pharmaceutically acceptable salts, hydrates, orprodrugs thereof, or combinations thereof, is administered to a parasitein order to sensitize the parasite to another drug or combination ofdrugs and/or to inhibit the parasite. The composition can be anycomposition described above. In certain embodiments, the composition canbe administered with any other drug or drugs which can alternatively bepresent in a pharmaceutical composition as described herein. Forexample, the other drug can include ivermectin.

In methods in which a parasite is sensitized to a drug or drugs, thedrug or drugs can be any drug or drugs for which rifamycin or arifamycin derivative, such as rifabutin or a rifabutin derivative, orrifampicin or a rifampicin derivative, or a pharmaceutically acceptablesalt, hydrate, or prodrug thereof, or a combination thereoone or morearylphenoxypropionate derivatives, one or more aryloxyphenoxyacetatederivatives, one or more aryloxyphenylacetate derivatives, one or moresubstituted quinols, or pharmaceutically acceptable salts, hydrates, orprodrugs thereof, or combinations thereof, increase sensitivity in aparasite. In certain embodiments, the drug or drugs can include anantiparasitic drug. Example types of suitable antiparasitic drugs anddrug combinations include antinematodic drugs, anticestodic drugs,antitrematodic drugs, antiamamoebic drugs, antiprotazoal drugs,antihelminthic drugs, tiniacides, antiprotozoic drugs, and other drugs.Example classes of suitable antiparasitic drugs include benzimidazoles,avermectins, milbemycins, piperazines, octadepsipeptides, thiophenes,pamoates, spiroindoles, imadazothiazoles, quinines, biguanides,sulfonamides, tetracyclines, lincomycins, alkaloids, carbamates,formamidines, organophosphates, Rifampin, Amphotericin B, Melarsoprol,Eflornithine, Miltefosine, Metronidazole, Tinadadazole,Quinine-pyrithamine-sulfadiazine, Trimethoprin-sulfa methoxazole,Piperazine, Praziquantel Triclabendazole, Octadepsipeptides, AminoAcetonitrile derivatives and derivatives thereof.

Exemplary suitable antiparasitic drugs for use with the compositions andmethods of the present disclosure include, without limitation,ivermectin, selamectin, doramectin, abamectin, albendazole, mebendazole,thiabendazole, fenbendazole, triclabendazole, flubendazole,diethylcarbazamine, niclosamide, suramin, pyrantel pamoate, levamisole,praziquantel, emodepside, monepantel, derquantel, rifoxanide,artemether, quinine, quinidine, chloroquine, amodiaquine, pyrimethamine,proguanil, sulfadozine, mefloquine, atovaquone, primaquine, artemisinin,doxycycline, clindamycin, sulfadoxine-pyrimethamine, moxidectin,permethrin, hexylresorcinol, and combinations thereof.

Accordingly, in certain embodiments, the antiparasitic drug or drugs towhich sensitivity is increased in a parasite by the one or morearylphenoxypropionate derivatives, one or more aryloxyphenoxyacetatederivatives, one or more aryloxyphenylacetate derivatives, one or moresubstituted quinols, or pharmaceutically acceptable salts, hydrates, orprodrugs thereof, or combinations thereof, can include, withoutlimitation, one or more of the antiparasitic drugs listed in Table 2below, or any class or type referred to therein, or any antiparasiticdrug referred to herein.

TABLE 2 Antiparasitic Drugs Antiparasitic Drug Class/TypeMechanism/Target Trimethoprim Anti-folate Dihydrofolate reductase(“DHFR”) Pyrimethamine (Daraprim) Proguanil (Paludrine) Sulfamethoxazoledeoxyhypusine synthase (“DHPS”) Sulfadiazine Sulfadoxine Atovaquone(Mepron) Ubiquinone Analog Perturbs Mitochondrial Electron TranspotSpiramycin (Rovmycin)- Antibiotic Ketolide Protein Synthesis InhibitorAzithromycin (Zithromax)- Macrolide Protein Synthesis InhibitorParomomycin (Humatin)- Aminoglycoside Protein Synthesis InhibitorClindamycin (Cleocin)- Lincosamide Protein Synthesis InhibitorTetracycline (Sumycin)- Polyketide Protein Synthesis InhibitorDoxycycline (Vibramycin)- Polyketide Protein Synthesis InhibitorMetronidazole (Flagyl) Nitroimidazole PFOR-Dependent RNS GenerationTinidazole (Tindamax) Nitazoxanide (Alinia) Nitrothiazole Iodoquinol(Yodoxin) Quinoline Iron chelation Chloroquine Hemozoin InhibitorPrimaquine Mefloquine Quinine Quinidine Praziquantel (Biltride)^(1,2)Paralytic Oxaminquine (Vansil)¹ Triclabendazole (Egaten)¹ BenzimidazolePrevents tubulin polymerization Niridazole¹ Thiazole ParalyticPhosphofructokinase Inhibitor Stibophen¹ Arylsulfonate Trichlorfon¹Organophosphate Paralytic ACE Inhibitor Mebendazole (Vermox)^(2,3)Benzimidazole Prevents tublin polymerization Albendazole (Albenza)^(2,3)Niclosamide² Salicylanilide Decouples Oxidative PhosphorylationIvermectin (Stromectol, Macroyclic Lactone Paralytic GABA AgonistMectizan)^(3,4) Doxycycline (Vibramycin)³ Antibiotic Targets SymbioticBacteria in Parasite Gut Diethylcarbamazine (DEC)³ Piperazine PerturbsArachidonic Acid Metabilism Pyrantel Pamoate (Helmex)³Tetrahydropyrimidine Paralytic Permethrin (Elimite, Nix)⁴ PyrethroidNeurotoxin via Na-Channel Binding Tiabendazole^(3,5) NitrothiazoleFumarate reductase Levamisole^(3,5) Imidazothiazole Paralytic Achagonist Mibemycin³ Macrolide Glutamate sensitive chloride channels¹Anti-trematodal; ²Anti-cestodal; ³Anti-nematodal; ⁴Anti-ectoparasitic;⁵Anti-helminthic

In methods of the current disclosure, the parasite can be sensitized toa drug or drugs already known to inhibit the parasite, or it can besensitized to a drug or drugs not previously used with that type ofparasite. If the parasite is a drug-resistant parasite that has acquiredor evolved a resistance to a drug, it can be sensitized to a drug thatpreviously exhibited a decreased ability to inhibit the parasite. Incertain embodiments, sensitization of the parasite to the drug occurs atleast in part by P-gp inhibition.

In certain embodiments, the composition can directly inhibit theparasite instead of or in addition to causing drug-sensitization.

The parasite that undergoes drug-sensitization or inhibition can be anytype of parasite. It may, for instance, be a helminth, such as anematode, a trematode, or a cestode, a protozoa, or an arthropod (i.e.,an ectoparasite). The parasite can be a parasite of any animal or plant.By way of example and not limitation, the parasite that undergoesdrug-sensitization or inhibition can be a species of the genusPlasmodium, such as Plasmodium falciparum, Plasmodium malariae,Plasmodium ovale, and Plasmodium vivax, a species of the genus Ascaris,such as Ascaris lumbricoides, a species of the genus Enterobius, such asEnterobius vermicularis, a species of the genus Trichinella, such asTrichinella spiralis, a species of the genus Haemonchus, such asHaemonchus contortus, a species of the genera Aphelenchoides,Ditylenchus, Globodera, Heterodera, Longidorus, Meloidogyne, Nacobbus,Pratylenchus, Trichodorus, and Xiphinema, a species of the genusBursaphelenchus, such as Bursaphelenchus xylophilus, a species of thegenus Fasciola, such as Fasciola hepatica, a species of the genusCoccidoides, or a species of the genus Onchocerca, such as Onchocercavolvulus.

The parasite that undergoes drug-sensitization or inhibition can be anyparasite. The parasite can be, for example, any parasite commonlyreferred to or known as a flea, a tick, a worm, a hookworm, a roundworm,a heartworm, a fluke, a mite, a spider, a beetle, a mosquito, a fly, ora bed bug.

Accordingly, in certain embodiments, the parasite that undergoesdrug-sensitization or inhibition can be a protozoan parasite, such as,for example, the protozoan parasites of Table 3 below. In certainembodiments, the parasite that undergoes drug sensitization orinhibition can be a helminthic parasite (parasitic worm) such as, forexample, the helminthic parasites of Table 4 below. In certainembodiments, the parasite that undergoes drug sensitization orinhibition can be an ectoparasite, such as, for example, the helminthicparasites of Table 5 below. In certain embodiments, multiple parasitesof different species, genera, class, or other category cansimultaneously undergo drug sensitization or inhibition in a single hostharboring the multiple parasites.

TABLE 3 Representative Protozoan Parasites Parasite Disease Symptoms(humans) Current Drug Regimen Cryptosporidium CryptosporidiasisDiarrhea-causing parasites Uncomplicated: Nitazoxanide hominis, parvum(typically asymptomatic) but (Alinia) deadly in susceptible pop. AIDS:Paromomycin (Humatin) w/ (AIDS, Children, etc.) Azithromycin (Zithromax)Questionable Efficacy for both regimes. Isosporiasis belli IsosporiasisDiarrhea-causing parasites #1: Trimethoprim-Sulfamethoxazole (typicallyasymptomatic) but w/folinic acid (Leucovorin) deadly in susceptible pop.#2: Pyrimethamine (Daraprim) w/ (AIDS, Children, etc.) folinic acid(Leucovorin) Cyclospora Cycosporiasis Diarrhea-causing parasitesUncomplicated: No Recognized cayetanesis (typically asymptomatic) butEffective Treatment deadly in susceptible pop. AIDS: Trimethoprim-(AIDS, Children, etc.) Sulfamethoxazole w/folinic acid (Leucovorin)considered effective at reducing severity. Control HIV infection toresolve parasite infestation. Toxoplasma Toxoplasmosis Usuallyasymptomatic but Uncomplicated: Pyrimethamine gondii causes fatalencephalitis in (Daraprim) + AIDS/Immunocompromisedsulfadiazine/clindamycin (Cleocin)/ Patients. TORCH Pathogenazithromycin (Zithromax) associated with transplacental Pregnancy:Uncomplicated + infection. Spimmycin (Rovamycin) AIDS: Pyrimethamine(Damprim) + sulfadiazine/clindamycin (Cleocin)/ azithromycin(Zithromax). Treat patient indefinitely once Dx. *** All regimes requirefolinic acid (Leucovorin) *** Balantidium coli Balantidiasis Diarrhea,Constiption. Can #1: Tetracycline (Sumycin) mimick inflammatory bowel#2: Metronidazole (Flagyl) conditions. #3: Iodoquinol (Yodoxin)Entamoeba Amebiasis Typically asymptomatic but Asymptomatic. LuminalAgents histolytica, can cause wide range of Iodoquinol (Yodoxin) ordispar symptoms ranging from mild paromomycin (Humatin) diarrhea tosevere dysentery Symptomatic: Colitis & Hepatic with mucoid, bloodyAbscess Metronidazole (Flagyl) + diarrhea. May cause ameobic LuminalAgents. liver abscesses w/ or w/o intestinal disease. Giardia lambliaGiardiasis ⅔ Asymptomatic. Others Metronidazole (Flagyl) experiencediarrhea varying in severity, sulfurous gas/belches, weight loss,cramping, pain, etc. Traveler's Diarrhea. Trichmonas Trichomoniasis Verycommon STI that is #1 Metronidazole (Flagyl) vaginalis usuallyasymtomatic but can #2 Tinidazole (Tindamax) cause vaginits, urethritis,etc. Dientamoeba Dientamoebiasis Traveler's diarrhea, chronicProphylaxis: Paromomycin fragilis diarrhea/abdominal pain, (Humatin)failure to thrive. Symptomatic: Iodouinol (Yodoxin), Paromomycin(Humatin), Tetracycline (Sumycin), Metronidazole (Flagyl) combination ofany two. Blastocystis Blastocystosis Typically nonsymptomaticMetronidazole (Flagyl) now hominis and colonization transient.considered ineffective. Nitazoxanide Nonspecific GI symptoms (Alinia)possible replacement (trials including diarrhea, ongoing) flatulence,pain, etc. Plasmodium Malaria Classical paroxysm (cyclic HemozoinInhibitors: Chloroquine falciparum, vivax, fevers) w/headache, joint(I), Primaquine (II), Mefloquine (I), ovale, malariea pain, vomiting,hemolytic Quinine (I), Quinidine Gluconate (I). anemia, jaundice, andAntifolates: sulfadoxine (I), convulsions. Neurologicalsulfamethoxypyrazine (I) + proguanil signs in severe cases. (II) orpyrimethamine (I). Presents 1-3 weeks post Sespuiterpene Lactones:infection w/o prophylaxis. Artemether, Artesunate, Dihyroartemisin,Artemotil, Artemisin (II) None FDA Approved. Naphthopuinonones:Atovaquone (II) Adjuncts: Tetracycline/Doxycycline, Clindamycin(Lincosamides). Proven Schizoticides. Use when indicated for SevereDisease. Babesia Babesiosis Typically asymptomatic Mild/Moderate:Atovaquone divergens, (>50%) with others (Mepron) w/Azithromycinmicrofti, other developing malaria-like (Zithromax) illness w/ hemolyticanemia, Severe: Quinine Sulfate w/ cyclic fevers, Clindamycin (Cleocin)thrombocytopenia, and possible organ failure 1-4 weeks post infection.Trypanosoma African Hemolymphatic phase with No CNS T.b. rhodesiense:Suramin brucei Trypanosomiasis fever, headache, pains, and No CNS T.b.gambiense: (Sleeping Sickness) fever followed by CNS Pentamidineinvolvement. Fatal if not CNS T.b. rhodesiense: Melarsoprol treatedpromptly. (Mel B, Arsobal) CNS T.b. gambiense: Eflomithine (DFMO,Ordinyl) Trypanosoma American Acute disease usually #1: Nifurtimox(Lampit) cruzi Trypanosomiasis asymptomatic but #2: Benzidazole(Rohagan) (Chaga's Disease) cagoma/Romana's Sign may Both drugs caneffect radical cure in be present. Chronic infection acute phase butbecome less effecitve destroys myenteric complex in chronic patients(especially those causing megaesophaug, who have been infected forlonger colon, other dilations and periods of time) dilatedcardiomyopathy. Leishomania Leishmaniasis Cutaneous, mucocutaneous,Classical Tx: Sodium Stibogluconate + mexicana, difffuse cutaneous, andpentavalent antimony (Pentostam) aethiopica, tropic, viseral (Kala Azar)w/meglumine antimonate braziliensis, Presentations (Glucontime). Retireddue to tox & donovani, resistance. infantum. Cutaneous Local: Topicalparomomycin + gentamicin formulation. Oral Systemic: Miltefosine(Impavido) w/azoles ketoconazole, itraconazole, fluconazole IV Systemic:Amphotericin B (Ambisome)

TABLE 4 Representative Helminthic Parasites Parasite Disease Symptoms(humans) Current Drug Regimen Schistosoma Schistosomiasis Direct skinpenetration in Praziquantel (Biltride) mansoni, aquatic soils, etc. withjaponicum, infected fresh-water snails haemotobium resulting inprolonged colonizationof the intestines/urinary tract dependent onspecies. Causes malnutiriton, organ damage, and associated with bladdercancer. Trichobilharzia Swimmer's Itch Direct skin penetration inAntihistamines regenti aquatic soils, etc. with No specific treatmentinfected fresh-water snails. Mild w/localized skin irritation.Clonorchis Clonorchiasis Following ingestion of raw #1: Praziquantel(Biltride) simensis fish, colonize biliary tract. #2: AlbendazoleAssociated with cholangiocarcinoma, liver damage, etc. Fasciolahepatica, Fascioliasis Liver dysfunction, pain Triclabendazole (Egaten)gigantica following colonization of the liver and biliary tractOpisthorchis Opisthorchiasis Following ingestion of raw #1: Praziquantel(Biltride) viverrinil fish, colonize biliary tract. #2: AlbendazoleAssociated with cholangiocarcinoma, liver damage, etc. ParagonimusParagonimiasis Liver, Lung dysfunction w/ #1: Praziquantel (Biltride)westermani, pulmonary manifestations in #2: Triclabendazole (Egaten)kellicotti chronic infections. Fasciolopsis Fasciolopisiasis Typicallyasymptomatic but Praziquantel (Biltride) buski can include diarrhea,abdominal pain, obstruction. Metagonimus Metagonimiasis Diarrhea, colic,obstruction. Praziquantel (Biltride) yokagawai HeterophyesHeterophyiasis Diarrhea, colic, obstruction. Praziquantel (Biltride)heterophyes Echinococcus Echinocccosis Typically asymptomatic withCystic: Albendazole (Albenza) w/ granulosus, formation of large cystsSurgical resection of cysts. Add multilocularis containing parasites.Rupture Praziquantel (Biltride) if cyst spillage results in allergicoccurs during surgery. reaction/anaphylaxis. Can Alveolar: Albendazole(Albenza) or behave like slow-growing Mebendazole (Vermox) destructivetumors. Taenia saginata, Taeniasis Tapeworms acquired from Praziquantel(Biltride) solium, asiatica eating undercooked beef and sizes causingmalnutrition, obstruction, etc. Taenia solium, Cysticerosis Occurfollowing infection Praziquantel (Biltride) w/prednisone asiatica withpork tapeworms. All tissues susceptible to cyst infestation. CNS/CVSmost dangerous. Hymenolpeis Hymenolepiasis Asymptomatic dwarf #1:Praziquantel nana, diminuta tapeworm. Extremely #2: Niclosamide common.#3: Nitazoxanide Diphyllobotrium Diphyllobothriasis Freshwater fishtapeworm. Praziquantel latum, Largest of all tapeworms and mansonoidescan cause obstruction, B12 def. w/ megaloblastic anemia. SpirometraSparganosis Asymptomatic unless woms No drug treatment. Surgical removalerinaceieuropaei migrate to CNS. Typically of worms required.nonspecific skin irritation as worms migrate. Dracunculus DracunculiasisGuinea Worms. Enough said, No drug treatment. “Stick Therapy” medinensisto remove erupting worms from lower extremities. OnchocercaOnchocerciasis River Blindess Ivermectin (Stromectol) & volvulusDoxycycline (Vibramycin) Loa loa Loiasis Asymptomatic Eye WormDiethylcarbamazine Mansonella Mansonellosis Swelling, nonspecific skin#1: Mebendazole (Vermox) or perstans, ozzardi, symptoms, rashes,typically Albendazole (Albenza) streptocera asymptomatic. #2: Ivermectin(Stromectol) *** Include doxycycline (Vibramycin) w/#1 or #2 ***Wucheria Lymphatic Typically asymtomatic but Ivermectin (Stromectol) w/bancrofti, Brugia Filariasis some develop profound Deithylcarbamazine(DEC) Typically malayi, timori lymphatic obstruction and responds poorlyto drugs once lymphadema (Elephantiasis) lymphedema sets in. w/episodesof febrile/afebrile lymphangitis and lymphadenitis. Nocturnal coughassociated with migrating worms. Gnathostoma Gnathostomiasis Painful,intermittent, itchy #1: Ivermectin (Stromectol) spinigerum, swellingscaused by #2: Albendazole (Albenza) hispidium migrating worms. PossibleVLM organism. Ancylostoma Ancylostomiasis Signs of iron-deficiency #1:Albendazole (Albenza) duodenale, and Cutaneous anemia, malnutrition, and#2: Mebendazole (Vermox) brazilienes Larva Migrans skin manifestationsfollowing #3: Pyrantel Pamoate (Helmex) infection by penetration ofintact skin from infected soil. (Hookworms) Necator Necatoriasis Signsof iron-deficiency #1: Albendazole (Albenza) americanus anemia,malnutrition, and #2: Mebendazole (Vermox) skin manifestations following#3: Pyrantel Pamoate (Helmex) infection by penetration of intact skinfrom infected soil. (Hookworms) Angiostrongylus AngiostrongyliasisAbdominal disease and #1: Albendazole (Albenza) cantonensis eosinophilicmeningitis #2: Mebendazole (Vermox) presentations possible. ***w/prednisolone *** Ascaris Ascariasis Typically asymptomatic w/ #1:Abendazole (Albenza) lumbricoides nonspecific respiratory #2:Mebendazole (Vermox) symptoms during pulmonary #3: Ivermectin(Stromectol) stage followed by adominal pain and possible obstrcution ofbiliary tract and/or intestines. Toxocara canis, Toxocariasis andTypically asymptomatic. #1: Ivermectin (Stromectol) cati Visceral LarvaVLM very serious depending #2: Albendazole (Albenza) Migrans on whatorgan is invaded. Non-VLM show generalized signs of worm infestations.Strongyloides Strongyloidiasis Typically asymptomatic w/ #1: Mebendazole(Vermox) stercoralis mild GI symptoms including #2: Albendazole(Albenza) pain and diarrhea. May present with rashes. EnterobiusEnterobiasis Typically asymptomatic w/ #1: Albendazole (Albenza)vermicularis pruitic perianal region and #2: Mebendazole (Vermox)possible superinfections. #3: Pyrantel Pamoate (Helmex) TrichinellaTrichinellosis Acquired from undercooked #1: Mebendazole (Vermox)spiralis pork resulting in tissue #2: Albendazole (Albenza) infestationfollowing actue GI symptoms. Larval encystments cause organ- specificsymptoms. Trichuris Trichuriasis Typically asymptomatic but #1:Mebendazole (Vermox) or trichiura heavy infections may cause #2:Albendazole (Albenza) GI symptoms. #3: Ivermectin (Stromectol)

TABLE 5 Representative Ectoparasites Parasite Disease Symptoms (humans)Current Drug Regimen Pedicululs Pediculosis Head lice, body lice spreadPermethrin (Elimite, Nix, Acticin, humanus by direct contact with eitheretc.) OTC any 1% formulation capitus, infected persons or infestedtopical only. humanus bedding, clothing, hats, etc. PhthiriasisPhthiriasis Pubic lice or “Crabs” spread Permethrin (Elimite, Nix,Acticin, pubis by direct contact (sexual). etc.) OTC any 1% formulationtopical only. Sarcoptes Scabies Mite infests stratum #1: Rx Permethrin(Elimite, scabiei corneum with reaction Lyclear, Nix) Any 5%formulation. resulting immune #2: Crotamiton (Eurax, Crotan) formingitchy #3: Lindane 1% blisters/lesions. #4 Ivermectin (Stromectol) forNorwegian variant.

The organism may also be Eimeria vermiformis.

The composition can be delivered to the parasite in a host organism bydelivering the composition to the host organism, such as byadministering, feeding, injecting, topical application, attachment, orproviding for inhalation. In certain embodiments, the compositioncontacts the parasite by diffusion throughout the host organism afteradministration. Additionally or alternatively, the composition can bedelivered to a recipient prophylactically, i.e., prior to recipientinfection, or contact with, or exposure to, the parasite. The mode ofdelivery can be selected based on a number of factors, includingmetabolism of one or more arylphenoxypropionate derivatives, one or morearyloxyphenoxyacetate derivatives, one or more aryloxyphenylacetatederivatives, one or more substituted quinols, or pharmaceuticallyacceptable salts, hydrates, or prodrugs thereof, or combinationsthereof, or another drug in the composition, the mode of administrationof other drugs to the host organism, such as the drug to which theparasite is sensitized, the location and type of parasite to bedrug-sensitized, the health of the host organism, the ability orinability to use particular dosing forms or schedules with the hostorganism, preferred dosing schedule, including any adjustment to dosingschedules due to side effects of other drugs, and ease ofadministration. In certain embodiments, the mode of administration canbe enteral, such as orally or by introduction into a feeding tube. Incertain embodiments, the mode of administration can be parenteral, suchas intravenously. In certain embodiments, the mode of administration istranscutaneous. In certain embodiments, the mode of administration istopical. In certain embodiments, the mode of administration is byaffixing a dosage form to the to body of an infected or susceptibleanimal, such as a collar or tag.

The dosage amounts of the and administration schedule of the one or morearylphenoxypropionate derivatives, one or more aryloxyphenoxyacetatederivatives, one or more aryloxyphenylacetate derivatives, one or moresubstituted quinols, or pharmaceutically acceptable salts, hydrates, orprodrugs thereof, or combinations thereof, can vary depending on othercomponents of the composition and their effects on drug availability ina recipient, the type of drug or drugs to which the parasite issensitized, the intended mode of administration, the intended schedulefor administration, when other drugs are administered, any drug toxicityconcerns, and the recipient's response to the drug. In certainembodiments, the amount and frequency of delivery of one or morearylphenoxypropionate derivatives, one or more aryloxyphenoxyacetatederivatives, one or more aryloxyphenylacetate derivatives, one or moresubstituted quinols, or pharmaceutically acceptable salts, hydrates, orprodrugs thereof, or combinations thereof, can be such that levels inthe recipient remain well below levels at which toxicity to therecipient becomes a concern. However the amount and frequency can alsobe such that the levels of one or more arylphenoxypropionatederivatives, one or more aryloxyphenoxyacetate derivatives, one or morearyloxyphenylacetate derivatives, one or more substituted quinols, orpharmaceutically acceptable salts, hydrates, or prodrugs thereof, orcombinations thereof, in the recipient remain continuously at a levelsufficient to induce drug-sensitization or are at a level sufficient toinduce drug sensitization when or shortly after the drug to which theparasite is sensitized is delivered to it. Accordingly, the compositioncan be taken on a regular basis during treatment with the drug to whichthe parasite is sensitized or it can be taken only a set time before, atthe same time, or a set time after the drug to which the parasite issensitized.

In certain embodiments, the administration of the arylphenoxypropionatederivative, aryloxyphenoxyacetate derivative, aryloxyphenylacetatederivative, substituted quinol, or pharmaceutically acceptable salt,hydrate, or prodrug thereof, or combination thereof, is calibrated toreach a threshold concentration in the plasma or tissue of a patient.Such calibration can take into consideration experimentally derivedbioavailability, such as the exemplary study data provided below, aswell as the mass of the patient. In certain embodiments, the thresholdconcentration is a proportion of the minimum inhibitory concentration(MIC₅₀).

In certain embodiments, and based on one or more of the considerationsdiscussed, the unit dosage of the arylphenoxypropionate derivative,aryloxyphenoxyacetate derivative, aryloxyphenylacetate derivative,substituted quinol, or pharmaceutically acceptable salt, hydrate, orprodrug thereof, or combination thereof, is between about 1 mg/kg bodyweight to about 500 mg/kg body weight. In certain embodiments, the unitdosage is between about 5 mg/kg to about 350 mg/kg. In certainembodiments, the unit dosage is between about 10 mg/kg and about 200mg/kg body weight.

The present disclosure further includes methods of identifying whetheran arylphenoxypropionate derivative, aryloxyphenoxyacetate derivative,aryloxyphenylacetate derivative, substituted quinol, or pharmaceuticallyacceptable salt, hydrate, or prodrug thereof, or combination thereof, isable to inhibit a parasite. Such methods include preparing or obtainingsuch a derivative, applying it to the parasite, and identifying that thederivative inhibits the parasite.

Representative MIC₅₀ data for certain arylphenoxypropionate derivativesin Cryptosporidium parvum (CP) are provided below. In certainembodiments, the arylphenoxypropionate derivative, aryloxyphenoxyacetatederivative, aryloxyphenylacetate derivative, substituted quinol, orpharmaceutically acceptable salt, hydrate, or prodrug thereof, orcombination thereof, has an MIC₅₀ value against CP of about 0.01 μM toabout 20 μM, or about 0.1 μM to about 15 μM, or about 0.5 μM to about12.5 μM, or about 1 μM to about 10 μM.

EXAMPLES

The following examples are provided to further illustrate certainembodiments of the disclosure. They are not intended to disclose ordescribe each and every aspect of the disclosure in complete detail andshould be not be so interpreted. Unless otherwise specified,designations of cells lines and compositions are used consistentlythroughout these examples.

Example 1—Synthesis of Aryloxyphenoxyacetate Derivatives

Aryloxyphenoxyacetate derivatives can be prepared according thefollowing scheme:

The compounds (3) are synthesized by condensation of hydroquinone (1)with chloro- or bromo-substituted acetate (2) at a temperature rangefrom 5° C. to 120° C. in water, or organic solvent, such as DMF, DMSO,ethanol, in the presence of base, such as NaOH, K₂CO₃, or NaH.Substitution of compounds (3) with aromatic chloride or bromide (R4-X)in organic solvent, such as DMF, DMSO, dioxane, acetonitril, ethanol inthe presence or absence of a catalyst, such as CuI, at a temperaturerange from 25° C. to 150° C. in the presence of base, such as K₂CO₃.Li₂CO₃, LiOH, KOH, produces ester (4). Hydrolysis of ester (4) will giveacid (5). Coupling of acid (5) with amine in the presence of couplingreagents, such as EDCI, CDI or via acyl chloride in organic solvent,such as DCM, THF, DMF, produces amide (6).

Other aryloxyphenoxy or aryloxyphenyl -acetate, -acetyl amide, -acylsulfonamide can be prepared by similar methods. It is apparent to oneskilled in art that other sequence of the reactions, and alternativereagents can be used for the synthesis of compounds of the presentdisclosure. These alternatives for the synthesis of the derivatives arewithin the scope of this invention.

Aryloxyphenyl urea or cabamate derivatives can be prepared according thefollowing schemes:

The compound (8) are synthesized by reaction of aminophenol (7) withisocyanate in organic solvent, such as DMF, dioxane, acetonitril,ethanol, THF, methanol, ethyl acetate, dichloromethane, or toluene, inthe presence or absence of base, such as K2CO3, NaHCO3, triethylamine ata temperature range from 5° C. to 120° C. Substitution of compounds (8)with aromatic chloride or bromide (R4-X) in organic solvent, such asDMF, DMSO, dioxane, acetonitril, ethanol in the presence or absence of acatalyst, such as CuI, at a temperature range from 25° C. to 150° C. inthe presence of base, such as K₂CO₃. Li₂CO₃, LiOH, KOH, producesAryloxyphenyl urea derivatives (9).

Example 2—Cryptosporidium Testing

Cell Culture Model of Cryprosporodium parvum Infection

Fresh oocysts of CP (Iowa strain) were purchased from Bunch Grass Farm(Deary, ID). Oocysts were further purified by a Percoll-based gradientcentrifugation method and surface sterilized with 10% bleach for 7 minon ice, followed by washes with phosphate-buffered saline (PBS). Anileocecal colorectal adenocarcinoma cell line (HCT-8, ATCC # CCL-244)was used to host the growth of CP in vitro. One day before theinoculation, HCT-8 cells were seeded in 96-well plates (2.5×10⁴/well)containing RPMI 1640 medium supplied with 10% fetal bovine serum (200 μLmedium/well in all experiments) and allowed to grow overnight at 37° C.under 5% CO₂ atmosphere until they reached ˜90% confluence. For drugtesting, host cells were infected with 1.5×10⁴ oocysts per well (ratio˜1:3). After inoculation, parasite oocysts were allowed to undergoexcystation and invasion into host cells for 3 h at 37° C. Freeparasites and oocyst walls in the medium were removed from the plates byan exchange of the culture medium. Drugs at specified concentrationswere added into the culture at this time point (immediately after themedium exchange). Parasite-infected cells were then incubated at 37° C.for additional 41 h (total 44 h infection time). At least twoindependent experiments were conducted for every experimental condition,each including two replicates drugs and eight replicates for negativecontrols.

Preparation of Cell Lysates

Plates containing HCT-8 cells infected with CP for 44 h were firstcentrifuged for 10 min at 1000×g to ensure that free merozoites in themedium were firmly settled on the bottom of the wells. Medium wasremoved, followed by two gentle washes with PBS. For extracting totalRNA, 200 μL of ice-cold Bio-Rad iScript qRT-PCR sample preparationreagent (lysis buffer) (Bio-Rad Laboratories, Hercules, Calif.) wasadded into each well. Plates were sealed with heat sealing films andsubjected to vortex for 20 min. Plates were then incubated at 75° C. for15 min, followed by centrifugation (5 min, 2000×g) to settle down celldebris. Supernatants were used immediately in subsequent qRT-PCRreactions or the plates were stored at −80° C. until use.

Real-Time qRT-PCR Assay

The levels of 18S rRNA transcripts from CP and host cells (referred toas Cp18S and Hs18S) were detected by real-time qRT-PCR method usinggScript™ one-step SYBR green qRT-PCR kit (Quanta Biosciences,Gaithersburg, Md.). Cell lysates prepared as described above werediluted by 100 and 2000 folds for detecting Cp18S and Hs18S transcripts,respectively. Reactions were performed in hard-shell 384-well skirtedPCR plates (Bio-Rad Laboratories, Hercules, Calif.) (10 μL/well)containing 3 μL diluted cell lysate, 5 μL one-step SYBR green mastermix, 0.2 μl RT master mix and the following primers: Cp18S-1011F andCp18S-1185R primer pair for Cp18S rRNA, and Hs18S-1F and Hs18S-1R primerpair for Hs18S rRNA. Hs18S levels were used as controls and fornormalization.

Real-time qRT-PCR reactions were performed by a Bio-Rad CFX384 TouchReal-Time PCR Detection System. The reactions started with synthesizingcDNA at 50° C. for 20 min, followed by 5 min at 95° C. to denatureRNA-cDNA hybrids and deactivate reverse transcriptase, and 40two-temperature thermal cycles of PCR amplification at 95° C., 10 secand 58° C., 30 sec. At the end of PCR amplification, melting curveanalysis was performed between 65° C. to 95° C. At least 2 technicalreplicates were included in qRT-PCR reactions for each sample.

After qRT-PCR reactions were completed, amplification curves and meltingpeaks were examined to assess the quality and specificity of thereactions, followed by the computation of relative parasite loads basedon the cycle threshold (C_(T)) values of Cp18S and Hs18S transcripts aspreviously described. qRT-PCR was used to quantify parasite 18S rRNA andMIC₅₀ was determined by the amount of compound resulting in 50%reduction of parasite growth compated to the control. The % inhibition(% inh @ (μM)) was calculated using a standard curve. No toxicity to theHCT-8 monolayers was observed.

TABLE 6 Cyryptosporidium Inhibition Data Compound % inh @ (μM) MIC₅₀(μM) NZ-259 33% @ 10 uM >10 NZ-261 60% @ 10 uM ~10 NZ-274 15% @ 10 uM NANZ-278 ~0.25 NZ-289 88% @ 10 uM NZ-295 61% @ 10 uM NZ-302 60% @ 10 uM~10 NZ-310 83% @ 10 uM NZ-322 44% @ 0.9 uM NZ-327 0.007 to 0.022 NZ-33136% @ 0.05 uM NZ-332 ~2.5 NZ-364 0.12 NZ-365 0.025 NZ-366 0.05 NZ-36685% @ 0.05 uM <0.05 (peak 1) NZ-366 81% @ 0.05 uM <0.05 (peak 2) NZ-36863% @ 0.125 uM <0.125 NZ-369 0.05 to 0.08 NZ-369 0.07 (peak 1) NZ-369~0.2 (peak 2) NZ-370 0.05 to 0.06 NZ-371 0.15 to 0.23 NZ-372 0.085NZ-386 0.05 to 0.3  NZ-387 ~0.44 NZ-389 ~1.1 NZ-395 ~5 NZ-398 50% @ 10uM ~10 NZ-399 NA NZ-400 67% @ 10 uM ~10 NZ-401 3% @ 4 uM NA NZ-403 63% @10 uM ~10 NZ-409 ~0.44 NZ-410 94% @ 10 uM 2-10 NZ-411 75.7% @ 10 uMNZ-425 0.25 to 0.5  NZ-426 0.25 to 1   NZ-427 71% @ 0.25 uM <0.25 NZ-433~2 NZ-438 43% @ 0.25 uM 0.25 to 1   NZ-440 53% @ 10 uM ~10 NZ-446 1-4NZ-450 ~2 NZ-458 NA NZ-459 1 NZ-460 19% @ 5 uM NA NZ-464 0.05 to 0.27NZ-465 68% @ 0.25 uM <0.25 NZ-466 0.05 to 0.1  NZ-467 0.25-1   NZ-46982% @ 0.25 uM <0.25 NZ-471 89% @ 4 uM 1-4 NZ-472 ~1 NZ-475 0.06 NZ-476~0.5-1     NZ-477 0.05 to 0.17 NZ-479 ~0.5-1     NZ-481 1-4 NZ-484 ~1NZ-485 1-4 NZ-489 68% @ 0.25 uM <0.25 NZ-490 60% @ 0.25 uM ~0.25 NZ-4960.25 to 1   NZ-500 ~0.25 NZ-505 ~0.25 NZ-516 0.016 NZ-518 32% @ 0.45uM >0.45 NZ-521 0.25 NZ-522 0.022 to 0.045 NZ-528 0.45 to 0.9  NZ-52942% @ 0.45 uM >0.45 NZ-530 ~0.225 NZ-531 NZ-532 NA NZ-533 NA NZ-534 NANZ-535 0.225 to 0.45  NZ-536 NA NZ-538 0.054 NZ-539 0.057 NZ-541 0.081NZ-542 0.112 NZ-543 0.045 NZ-544 0.072 NZ-545 0.45 NZ-546 76% @ 0.225 uM<0.225 NZ-547 96% @ 0.056 uM <0.056 NZ-548 45% @ 0.112 uM 0.112 to 0.225NZ-553 0.002 NZ-554 0.056 to 0.112 NZ-555 79% @ 0.056 uM <0.056 NZ-55664% @ 0.056 uM ~0.056 NZ-557 0.112 to 0.225 NZ-558 ~0.056 NZ-561 0.04NZ-562 ~0.45 NZ-563 0.018 NZ-564 0.054 NZ-572 ~0.5 NZ-573 ~0.5 NZ-574 ~1NZ-575 ~1 NZ-576 ~0.03 NZ-577 ~0.25 NZ-578 0.018 NA: not active

In general, compounds with a benzothiazole core inhibited CP better thanthose with a benzopyrazine core. In additions, benzothiazole coressubstituted with 6-Cl inhibited CP better than benzothiazole cores witha 6-F or 5,6-di-f substitution. α-methyl substitution at phenyl aceticamides improved inhibition as compared to unsubstituted phenyl aceticamides, often decreasining MIC₅₀ to less than 100 nM.

Example 3—Additional Crytosporidium, Toxicity, Dosing, and Other Testing

Cell Toxicity Testing

S. cerevisiae cytotoxicity and human fibroblast cytotoxicity testing wasperformed. The following compounds were not toxic at concentrations ator above 100 μM in both S. cerevisiae cytotoxicity and human fibroblastcytotoxicity testing: NZ-251, NZ-274, NZ-287, NZ-289, NZ-290, NZ-293,NZ-294, NZ-295, NZ-296, NZ-298, NZ-299, NZ-300, NZ-301, NZ-302, NZ-304,NZ-305, NZ-306, NZ-307, NZ-308, NZ-309, NZ-310, NZ-311, NZ-312, NZ-313,NZ-314, NZ-315, NZ-316, NZ-317, NZ-318, NZ-319, NZ-320, NZ-321, NZ-322,NZ-323, NZ-325, NZ-326, NZ-327, NZ-328, NZ-329, NZ-330, NZ-331, NZ-332,NZ-334, NZ-335, NZ-337. NZ-361, NZ-362, NZ-363, NZ-364, NZ-369, NZ-370,NZ-371. NZ-373, NZ-374, NZ-376, NZ-377, NZ-378, NZ-379, NZ-380, NZ-381,NZ-383, NZ-385, NZ-386, NZ-387, NZ-388, NZ-389, NZ-390, NZ-391, NZ-392,NZ-393, NZ-394, NZ-395, NZ-396, NZ-397, NZ-398, NZ-399, NZ-400, NZ-401,NZ-402, NZ-403, NZ-404, NZ405, NZ-406, NZ-407, NZ-408, NZ-409, NZ-410,NZ-411, NZ-412, NZ-413, NZ-4 14, NZ-415, NZ-416, NZ-417, NZ-418, NZ-419,NZ-420, NZ-421, NZ-422, NZ-423, NZ-424, NZ-425, NZ-426, NZ-427, NZ-428,NZ-429, NZ-430, NZ-431, NZ-432, NZ-433, NZ-534, NZ-435, NZ-436, NZ-437,NZ-438, NZ-439, NZ-440, NZ-441, NZ-442, NZ-443, NZ-444, NZ-445, NZ-446,NZ-447, NZ-448, NZ449, NZ-450, NZ-451, NZ-452, NZ-453, NZ-454, NZ-455,NZ-456, NZ-457, NZ-458, NZ-459, NZ-460, NZ-461, NZ-462, NZ-463, NZ-464,NZ-465, NZ-466, NZ-467, NZ-468, NZ-469, NZ-470, NZ-471, NZ-472, NZ-473,NZ-474, NZ-475, NZ-476, NZ-477, NZ-478, NZ-479, NZ-480, NZ-481, NZ-481,NZ-482, NZ-483, NZ-484, NZ-485, NZ-486, NZ-487, NZ-488, NZ-489, NZ-490,NZ-491, NZ-492, NZ-493, NZ-494, NZ-495, NZ-496, NZ-497, NZ-498, NZ-499,NZ-500, NZ-501, NZ-502, NZ-503, NZ-504, NZ-505, NZ-506, NZ-507, NZ-508,NZ-509, NZ-510, NZ-511, NZ-512, NZ-513, NZ-514, NZ-515, NZ-516,NZ-517-NZ 578.

The following compounds were not toxic at concentrations at or above 100μM in S. cerevisiae cytotoxicity testing: NZ-347, NZ-349, NZ-350,NZ-351, NZ-353, NZ-355, NZ-356, NZ-357, NZ-358, NZ-359, NZ-360, NZ-372.

The following compounds were not toxic at concentrations at or above 100μM in human fibroblast cytotoxicity testing: NZ-303, NZ-338, NZ-341,NZ-342, NZ-343, NZ-345, NZ-346, NZ-368, NZ-365, NZ-382, fenoxaprop-p,fenoxaprop-p-ethyl.

The following compounds were not toxic at concentrations at or above 25μM and at or below 50 μM in S. cerevisiae cytotoxicity testing: NZ-348,NZ-352, NZ-366, NZ-368.

The following compound was not toxic at concentrations at or above 25 μMand at or below 50 μM in human fibroblast cytotoxicity testing: NZ-366.

The following compounds were not toxic at concentrations at or above 50μM and at or below 100 μM in S. cerevisiae cytotoxicity testing: NZ-336,NZ-354, NZ-365, NZ-382.

The following compound was not toxic at concentrations at or above 50 μMand at or below 100 μM in human fibroblast cytotoxicity testing: NZ-336.

A group of compounds found to be promising were subjected to furthertests. These tests included an IL-12 mouse model test to determinecompound efficacy, verification of MIC₅₀ for CP, cytotoxicity test forfibroblasts and yeast to determine potential toxic effects, a Humanether-a-go-go-related gene (hERG) test to determine potentialcardiotoxicity, an AMES test tp determine mutagenic potential, a SafetyScreen 44 test to determine common negative off-target drug interastion(Eurofins Cerep, SA, France), a cytochrome P450 (CYP) test to determinepotential liver toxicity, a maximum tolerated dose, test, aPharmacokinetics (PK) test to determine fate of the substanceadministered to a living organism tests for plasma stability in humanand mouse, to measure the degradation of compound in plasma MClint andHClint test to determine in vitro intrinsic clearance for Mouse andHuman, and kinetic solubility and plasma protein binding tests in mouseand human. Results are presented in Table 7.

TABLE 7 Basic Efficacy, Toxicity, and Dosing Test Results FibroblastYeast MCLint, Mouse MIC50 Cytotox Cytotox hERG HCLint Kinetic Model (nM)(IC50) (IC50) (Abbvie) (mL/min/g Sol. Compound (Mead) (CP) (uM) (uM)(uM) liver) (uM) PPB NZ-366 DPI7 = 59% 50 48 80 2.4 MLM = 41 62 98.1%@50 mg/kg HLM = 7.9 (mice) NZ-369 DPI7 = 70% 80 >100 >100 >30 MLM = 3.386 98.5% @100 mg/kg HLM = 0.69 (mice) NZ-516 DPI7 = 94% 16 5.6 >100 2.7MLM = 4.1 100 @50 mg/kg HLM = 0.54 NZ-370 50-60 >100 >100 30 MLM = 40HLM = NZ-365 25 >100 >100 12 MLM = 10 28 HLM = 4.8 NZ-327 7-22 >100 >100 MLM = 3.7 33 98.4% HLM = 1.3 (mice) NZ-538 54 >100 >1007.3 MLM = 3.9 HLM = 0.7 NZ-539 57 >100 >100 >30 MLM = 4.4 HLM = 1.8NZ-541 81 >100 >100 27 MLM = 6.3 HLM = 2.0 NZ-543 45 >100 >100 24.0 MLM= 2 HLM = 1.2 NZ-544 72 >100 >100 11.0 MLM = 3.3 HLM = 2.6 NZ-553  240 >100 11.0 MLM = 1.28 100  99% HLM = 0.87 (mice) NZ-578 <30  >100 83%@31 uM

Example 4—Efficacy of NZ-366 and NZ-369 in an acute CryptosporodosisMouse Model

To investigate the relationship between anticryptosporidial activity andsystemic exposure the plasma pharmacokinetics for NZ-369 were measured.Compound NZ-369 had excellent systemic pharmacokinetics, with thegreatest values of C_(max) and t_(1/2), for an overall area under thecurve (AUC).

The pharmacokinetics of NZ-369 following single intravenous (IV) andoral administration (PO) at 3 and 10 mg free base/kg respectively to thefemale Balb/c mouse. PK paremeters are presented in Table 8.

TABLE 8 PK Parameters for NZ-369 IV PO C_(max) (ng/mL) 2159 T_(max) (hr)2 T_(1/2) (hr) 3.4 AUC0-24 (mg-min/mL) 452102 1186472 Clb (mL/min/kg)6.6 Vdss 1.7 F (%) 78.8

The anticryptosporidial activity of the in vitro inhibitors was assessedin the IL-12 knockout mouse model that resembles the acute human disease(Ehigiator H N, Romagnoli P, Borgelt K, Fernandez M, McNair N, Secor WE, Mead J R. 2005. Mucosal cytokine and antigen-specific responses toCryptosporidium parvum in IL-12p40 KO mice. Parasite Immunol. 27: 17-28;Campbell L D, Stewart J N, Mead J R. 2002. Susceptibility toCryptosporidium parvum infections in cytokine- and chemokine-receptorknockout mice. J. Parasitol. 88:1014-1016). The protocol was approved bythe Institutional Animal Care and Use Committees of Emory University,the AtlantaVAMedical Center, and Brandeis University. Mice (6 to 10 pergroup) were inoculated with 1,000 purified CP oocysts (Iowa isolate,from cattle). Treatment by gavage began 4 h postinfection with eithervehicle (5% dimethyl sulfoxide (DMSO) in canola oil), 50-100 mg/kgcompound, or 2,000 mg/kg paromomycin. Compounds were given for 7 days,and mice were sacrificed on day 8 (peak infection). Parasite load wasquantified by fluorescence-activated cell sorting (FACS) assays for thepresence of the oocysts in the feces at days 0, 4, and 7. Fecal pelletsfrom individual mice were routinely collected daily and homogenized inadjusted volumes of 2.5% potassium dichromate. Samples were processedindividually. Aliquots (200 ul) of vortexed samples were processed overmicroscale sucrose gradients as previously described (Arrowood M J, HurdM R, Mead J R. 1995. A new method for evaluating experimentalcryptosporidial parasite loads using immunofluorescent flowcytometry. J.Parasitol. 81:404-409). The oocyst-containing fraction was collected,washed, and treated with monoclonal antibody (OW5O-FITC) for 20 min.Samples were adjusted to 600 ul, and a portion (100 ul) was assayed witha 102-s sampling interval using logical gating of forward/side scatterand OW5O-FITC fluorescence signal on a Becton, Dickinson FACScan flowcytometer. Flow cytometry data were evaluated by analysis of variance(KaleidaGraph (Synergy Software, Reading Pa.); Microsoft Excel(Microsoft Corporation, Redmond, Wash.)).

NZ-366 (50 mg/kg) and NZ-369 (100 mg/kg) were administered via gavage ina single daily dose to IL-12 knockout mice that were infected with 1,000CP oocysts. Additional control groups included those treated with singledaily doses of vehicle, and paromomycin (Prm) (2,000 mg/kg), by oralgavage. Fecal oocysts were counted on day 7 post infection and theseresults demonstrated that the two compounds, NZ-366 and NZ-369, haveanticryptosporidial activity in the acute IL-12 knockout mouse model ofdisease. Results are presented in FIG. 1. NZ-366 and NZ-369 were moreeffective than paromomycin, a current leading drug used to combat theparasite, when administered after a single dose, and equally aseffective as paromomycin over the course of the study. As expected therewas no overt toxicity noted in the mice. NZ-516, NZ-364, NX-475, andNZ-372 have also been shown to be effective in the same type of test.

Example 5—In Vivo Toxicity Evaluation of NZ-369

Compound toxicity was evaluated at 200 mg/kg of body weight inuninfected mice treated for 7 days (5 mice/group). Toxicity was assessedby weight loss and signs of distress (e.g., ruffled fur, hunchedshoulders, and decreased appetite). No overt signs of toxicity wereobserved for any of the compounds. No significant changes in weight wereobserved between treated and vehicle control mice

Example 6—Calf Studies of NZ-369

New born calves are susceptible to CP infection. They can develop severediarrhea like humans. Calves were inoculated with 5×10⁷ CP oocysts/calfon day 0. Calves had diarrhea in both the groups at onset of dosing.Treatment was started on day 3. Calves were given NZ-369 @ 8.5 mg/kgevery 12 hrs for 5 days. Fecal volume, urine volume, daily clinicalevaluation, fecal consistency scores and weight gains were evaluated.Results for fecal volume are presented in FIG. 2. The treatment andcontrol calves had about the same fecal volume for the first two days oftreatment, then the treatment calves treated with NZ-369 showed a markedreduction in fecal volume through day 8 post infection as compared tothe control.

Greater urine output was seen in calves treated with NZ-369 than incontrol calves except on day 4 post-infection as shown in FIG. 3. Calvesreceiving NZ-369 also had higher clinical evaluation scores and greaterimprovement post-infection as shown in FIG. 4.

A lower fecal consistency score, as shown in FIG. 5, was observed in theNZ-369 treated calved compared with control calves on days 4-7 postinfection, which demonstrates decreased diarrhea with NZ-369 therapy.

As shown in FIG. 6, calves treated with NZ-369 maintained their weightover the trial period compared to the control calf. Treatment calvesactually gained a slight amount of weight compared to the control calf.

Example 7—Eimeriosis Testing in Chickens

Eimeriosis, often also referred to as coccidiosis, is the disease causedby Eimeria parasites resulting in severe mucosal damage, weight loss andsometimes even death. The disease is widespread and many species arefound in poultry, livestock and small animals. Infections with Eimeriasp. confined to the distal ileum and/or the large bowel can often resultin intermittent diarrhoea or even be asymptomatic. Infections may ofteninvolve the pyloric region of the gastric mucosa. Parasite formsdisplace the microvillus border and eventually lead to the loss of themature surface epithelium. The rapid loss of surface epithelium causesmarked shortening and fusion of the villi and lengthening of the cryptsdue to acceleration of cell division to compensate for the loss ofcells. The combined loss of microvillus border and villus heightdiminishes the absorptive intestinal surface and reduces uptake offluids, electrolytes and nutrients from the gut lumen.

The pharmacokinetics of NZ-369 was first investigated in in broilerchickens. 9 male broiler chicks age 14-21 days were used in two studies,with triplicate time points. In the first study, chicks received 1-20 mgper animal (57 mg/kg) in 500 μL of 10% DMSO, 90% Canola oil by gavage.In the second study, chick received 2-40 mg per animal (117 mg/kg) in500 μL of 10% DMSO, 90% Canola oil by gavage.

3 male broiler chicks age 14-21 days were used a a third study withtriplicate time points. These chicks in the third study received 3-40 mgper animal (125 mg/kg) in a 240 mg NZ-369 plus 400 g blended bird feedfor two days per cohort. These chicks consumed the feed withoutprejudice, with most of it being eaten on day 1 such that dosing at 24hours was 0.9823 μg/mL and at 48 hours it was 0.3646 μg/mL.

All chicks tolerated the dose well without any obvious signs ofdistress, morbidity, or mortality.

To determine the effects of NZ-366 and NZ-369 on coccidiosis in broilerchicks, experimental animals were divided into 4 treatment groups:Unmedicated (UNM), those receiving the experimental compounds (366 and369); and those receiving Salinomycin (SAL).

Compounds NZ-366 and NZ-369 were administered at a dose of 20 mg/bird byoral gavage daily beginning from 11 days post-hatching. Salinomycin wasadministered in-feed beginning from 10 days post-hatching. Broilers wereadministered a 1000x dose of coccidiosis vaccine by oral gavage at 13days post-hatching.

Results for duodenal lesions, which result from coccidiosis, arepresented in FIG. 7. Lesion scores in the duodenum were lower in broilerchicks administered NZ-369 as compared to unmedicated broilers and thoseadministered NZ-366. Additionally, reduction of lesion scores by NZ-369was comparable to broiler chicks administered Salinomycin. Treatmentwith NZ-369 appeared to reduce lesion scores in the duodenum of broilerchicks to a level comparable to treatment with Salinomycin. Thereduction in lesion scores suggests the efficacy of NZ-369 and similarcompounds as anticoccidials for use in broiler chickens. In FIG. 7,lesion scores expressed as the mean±SEM from 24 broilers per treatment.Different letters indicate significantly different means as determinedusing Duncan's multiple range test (P<0.05)

Although only exemplary embodiments of the invention are specificallydescribed above, it will be appreciated that modifications andvariations of these examples are possible without departing from thespirit and intended scope of the invention. For example, variousspecific formulations including components not listed herein andspecific methods of administering such formulations can be developedusing the ordinary skill in the art. Numeric amounts expressed hereinwill be understood by one of ordinary skill in the art to includeamounts that are approximately or about those expressed. Furthermore,the term “or” as used herein is not intended to express exclusiveoptions (either/or) unless the context specifically indicates thatexclusivity is required; rather “or” is intended to be inclusive(and/or).

The invention claimed is:
 1. A method of sensitizing a parasite to adrug comprising administering an arylphenoxypropionate derivative, anaryloxyphenoxyacetate derivative, an aryloxyphenylacetate derivative,one or more substituted quinols, or a pharmaceutically acceptable salt,hydrate, or prodrug thereof, or a combination thereof to the parasite inan amount and for a time sufficient to sensitize the parasite to thedrug, wherein the parasite is a species of the genus Plasmodium, aspecies of the genus Ascaris, a species of the genus Enterobius, aspecies of the genus Trichinella, a species of the genus Haemonchus, aspecies of the genus Aphelenchoides, a species of the genus Ditvlenchus,a species of the genus Globodera, a species of the genus Heterodera, aspecies of the genus Longidorus, a species of the genus Meloidogyne, aspecies of the genus Nacobbus, a species of the genus Pratvlenchus, aspecies of the genus Trichodorus, a species of the genus Xiphinema, aspecies of the genus Bursaphelenchus, a species of the genus Fasciola, aspecies of the genus Coccidoides, or a species of the genus Onchocerca,or the parasite is selected from the group consisting of Pedicululshumanus, Phthiriasis pubis, Sarcoptes scabiei, Schistosoma mansoni,Schistosoma japonicum, Schistosoma haemotobium, Trichobilharzia regenti,Clonorchis simensis, Fasciola hepatica, Fasciola gigantica, Opisthorchisviverrinil, Paragonimus westermani, Paragonimus kellicotti, Fasciolopsisbuski, Metagonimus vokagawai, Heterophyes heterophyes, Echinococcusgranulosus, Echinococcus multilocularis, Taenia saginata, Taenia solium,Taenia asiatica, Hvmenolpeis nana, Hvmenolpeis diminuta, Diphvllobotriumlatum, Diphvllobotrium mansonoides, Spirometra erinaceieuropaei,Dracunculus medinensis, Onchocerca volvulus, Lo vaginalis a loa,Mansonella perstans, Mansonella ozzardi, Mansonella streptocera,Wucheria bancrofti, Brugia malavi, Brugia timori, Gnathostomaspinigerum, Gnathostoma hispidium, Ancylostoma duodenale, Ancylostomabrazilienes, Necator americanus, Angiostrongylus cantonensis, Ascarislumbricoides, Toxocara canis, Toxocara cati, Strongyloides stercoralis,Enterobius vermicularis, Trichinella spiralis, Trichuris trichiura,Cryptosporidium hominis, Cryptosporidium parvum, Isosporiasis belli,Cyclospora cavetanesis, Balantidium coli, Entamoeba histolvtica, dispar,Giardia lamblia, Trichmonas vaginalis, Dientamoeba fragilis,Blastocystis hominis, Plasmodium falciparum, Plasmodium vivax,Plasmodium ovale, Plasmodium malariea, Babesia divergens, Babesiamicrofti, Trypanosoma brucei, Trypanosoma cruzi, Leishomania mexicana,Leishomania aethiopica, Leishomania tropic, Leishomania braziliensis,Leishomania donovani, and Leishomania infantum, Eimeria vermiformis,Eimeria brunett, Eimeria praecox, Eimeria maxima, Eimeria mitis, Eimerianecatrix and Eimeria tenella.
 2. The method of claim 1, furthercomprising administering an arylphenoxypropionate derivative, anaryloxyphenoxyacetate derivative, an aryloxyphenylacetate derivative,one or more substituted quinols, or a pharmaceutically acceptable salt,hydrate, or prodrug thereof, or a combination thereof to the parasitebefore administering the drug to which the parasite is sensitized. 3.The method of claim 1, further comprising administering anarylphenoxypropionate derivative, an aryloxyphenoxyacetate derivative,an aryloxyphenylacetate derivative, one or more substituted quinols, ora pharmaceutically acceptable salt, hydrate, or prodrug thereof, or acombination thereof to the parasite concurrently with the drug to whichthe parasite is sensitized.
 4. The method of claim 1, further comprisingadministering an arylphenoxypropionate derivative, anaryloxyphenoxyacetate derivative, an aryloxyphenylacetate derivative,one or more substituted quinols, or a pharmaceutically acceptable salt,hydrate, or prodrug thereof, or a combination thereof to the parasiteafter administering the drug to which the parasite is sensitized.
 5. Themethod of claim 1, further comprising administering anarylphenoxypropionate derivative, an aryloxyphenoxyacetate derivative,an aryloxyphenylacetate derivative, one or more substituted quinols, ora pharmaceutically acceptable salt, hydrate, or prodrug thereof, or acombination thereof to the parasite a second or greater time.
 6. Themethod of claim 1, wherein administering an arylphenoxypropionatederivative, an aryloxyphenoxyacetate derivative, an aryloxyphenylacetatederivative, one or more substituted quinols, or a pharmaceuticallyacceptable salt, hydrate, or prodrug thereof, or a combination thereofto the parasite in an amount and for a time sufficient to sensitize theparasite to the drug comprises rendering the parasite susceptible to thedrug at a lower dose than in the absence of an arylphenoxypropionatederivative, an aryloxyphenoxyacetate derivative, an aryloxyphenylacetatederivative, one or more substituted quinols, or a pharmaceuticallyacceptable salt, hydrate, or prodrug thereof, or a combination thereof.7. The method of claim 1, wherein administering an arylphenoxypropionatederivative, an aryloxyphenoxyacetate derivative, an aryloxyphenylacetatederivative, one or more substituted quinols, or a pharmaceuticallyacceptable salt, hydrate, or prodrug thereof, or a combination thereofto the parasite in an amount and for a time sufficient to sensitize theparasite to the drug comprises rendering the parasite susceptible to adrug that the parasite would not be susceptible to in the absence of anarylphenoxypropionate derivative, an aryloxyphenoxyacetate derivative,an aryloxyphenylacetate derivative, one or more substituted quinols, ora pharmaceutically acceptable salt, hydrate, or prodrug thereof, or acombination thereof.
 8. The method of claim 1, wherein the drugcomprises an antiparasitic drug and wherein administeringarylphenoxypropionate derivative, an aryloxyphenoxyacetate derivative,an aryloxyphenylacetate derivative, one or more substituted quinols, ora pharmaceutically acceptable salt, hydrate, or prodrug thereof, or acombination thereof to the parasite in an amount and for a timesufficient to sensitize the parasite to the drug comprises rendering theparasite susceptible to death or a decrease in growth due to theantiparasitic drug.